ASCEND A randomized trial of omega-3 fatty acids (fish oil) versus - - PowerPoint PPT Presentation

ASCEND A randomized trial of omega-3 fatty acids (fish oil) versus placebo for primary cardiovascular prevention in 15,480 patients with diabetes

Jane Armitage and Louise Bowman

• n behalf of the ASCEND Study Collaborative Group

Funded by British Heart Foundation, UK Medical Research Council and support from Abbott, Bayer, Mylan and Solvay Designed, conducted and analysed independently of the funders University of Oxford is the trial sponsor

Background

• Diabetes increases cardiovascular risk, so a safe dietary

supplement that reduced risk would be of value

• Higher fish intake is associated with lower cardiovascular risk
• Omega-3 (n-3) fatty acid (FA) supplements recommended for

secondary prevention based on trials done in 1980s and 1990s

• Increased fish intake recommended for primary prevention
• Recent meta-analyses of randomized trials have not shown

benefits of omega-3 fatty acids in primary or secondary prevention

ASCEND trial design

Eligibility: Age ≥ 40 years; any DIABETES; no prior cardiovascular disease Participants: 15,480 UK patients Randomization: Omega-3 fatty acids 1 g capsule/day vs placebo (and aspirin 100 mg daily vs placebo) Follow-up: Mean 7.4 years; >99% complete for morbidity & mortality Adherence: Average adherence to omega-3 capsules 77% Streamlined methods: mail-based (questionnaires & treatment); no study clinics; electronic health records; 2x2 factorial design; highly cost-effective

ASCEND Study Collaborative Group. Trials 2016;17:286 / Am Heart J 2018;198:135-144

Baseline demographics (N=15,480)

Characteristic Omega-3 FA Placebo

Age, years 63 63 Male 63% 63% Type 2 diabetes 94% 94% Diabetes duration, median years 7 7 Hypertension 62% 62% Statin use 75% 76% Body Mass Index, kg/m2 31 31 Glycated haemoglobin, mmol/mol 55 (7.2%) 55 (7.2%)

Key outcomes

Primary efficacy outcome: Serious Vascular Event (SVE)

Non-fatal myocardial infarction, Non-haemorrhagic stroke or transient ischaemic attack, or Cardiovascular death (excluding any intracranial haemorrhage)

Secondary outcome: SVE or any revascularization

Pre-specified for subgroup analyses

Effect of omega-3 FA supplements on serious vascular events

1 2 3 4 5 6 7 8 9 5 10 15 20 Years of Follow-up Participants with Event (%) Placebo Omega-3 FA Rate ratio 0.97 (0.87-1.08) P=0.55 Placebo 712 (9.2%) Omega-3 FA 689 (8.9%)

Effect of omega-3 FA supplements on vascular events

0.6 0.8 1.0 1.2 0.97 (0.87–1.08) Omega-3 FA Better Placebo Better Rate Ratio (95% CI) Omega-3 FA Placebo (N=7740) (N=7740)

• no. of participants with events (%)

Non-fatal myocardial infarction Non-fatal presumed ischaemic stroke Transient ischaemic attack Vascular death excl. intracranial haemorrhage Any serious vascular event 186 217 185 186 689 (2.4) (2.8) (2.4) (2.4) (8.9) 200 214 180 228 712 (2.6) (2.8) (2.3) (2.9) (9.2) P = 0.55 1.00 (0.91–1.09) Any arterial revascularization Any serious vascular event or revascularization 368 882 (4.8) (11.4) 356 887 (4.6) (11.5) P = 0.92 Type of Event

Effects of omega-3 FA supplements on SVE or revascularization in different types of participant

0.6 0.8 1.0 1.2 1.4 1.6 0.99 (0.89–1.11) 1.00 (0.84–1.18) 0.94 (0.75–1.18) 1.10 (0.94–1.29) 0.94 (0.82–1.08) 0.97 (0.79–1.18) 1.13 (0.98–1.29) 0.86 (0.73–1.01) 1.00 (0.91–1.09) Omega-3 FA Better Placebo Better Rate Ratio (95% CI) Omega-3 FA Placebo (N=7740) (N=7740)

• no. of participants with events (%)

Sex Men Women Body mass index (kg/m²) <25 ≥25 <30 ≥30 5-year vascular risk <5% ≥5% <10% ≥10% All 614 268 143 320 393 192 427 263 882 (12.7) (9.2) (12.7) (11.5) (11.0) (6.1) (13.1) (19.8) (11.4) 617 270 152 291 418 195 388 304 887 (12.7) (9.3) (13.6) (10.6) (11.6) (6.2) (11.8) (22.7) (11.5) Baseline Characteristic

Effect of omega-3 FA supplements on cause-specific mortality

0.6 0.8 1.0 1.2 1.4 1.6 0.79 (0.61–1.02) 0.94 (0.59–1.50) 0.80 (0.57–1.12) 0.82 (0.68–0.98) 0.95 (0.82–1.12) 0.93 (0.68–1.28) 1.26 (1.00–1.59) 0.77 (0.41–1.45) 1.01 (0.90–1.14) 0.75 (0.17–3.31) 0.95 (0.86–1.05) Omega-3 FA Better Placebo Better Rate Ratio (95% CI) Omega-3 FA Placebo (N=7740) (N=7740)

• no. of participants with events (%)

Coronary All stroke Other vascular Vascular Cancer Respiratory Other medical External causes Non-vascular Unknown cause All-cause mortality 100 35 61 196 305 73 158 17 553 3 752 (1.3) (0.5) (0.8) (2.5) (3.9) (0.9) (2.0) (0.2) (7.1) (0.0) (9.7) 127 37 76 240 319 78 125 22 544 4 788 (1.6) (0.5) (1.0) (3.1) (4.1) (1.0) (1.6) (0.3) (7.0) (0.1) (10.2) Cause of Death

0.6 0.8 1.0 1.2 1.4 1.6 0.90 (0.75–1.07) 1.04 (0.79–1.37) 1.07 (0.91–1.25) 1.17 (0.87–1.58) 1.14 (0.86–1.52) 1.02 (0.70–1.48) 0.72 (0.42–1.22) 0.78 (0.46–1.31) 1.00 (0.91–1.10) Omega-3 FA Better Placebo Better Rate Ratio (95% CI) Omega-3 FA Placebo (N=7740) (N=7740)

• no. of participants with events (%)

Gastrointestinal Respiratory Genitourinary Haematological Breast Melanoma skin Other Unspecified Any cancer 226 104 323 94 103 55 23 25 894 (2.9) (1.3) (4.2) (1.2) (1.3) (0.7) (0.3) (0.3) (11.6) 251 100 303 80 90 54 32 32 890 (3.2) (1.3) (3.9) (1.0) (1.2) (0.7) (0.4) (0.4) (11.5) Type of Event

Effect of omega-3 FA supplements on site-specific cancer

Fish oil supplements are widely used

• Estimated global market for omega-3 products was $31 billion in 2015
• In a large UK prospective study, 31% of adults reported taking fish oils
• Estimates suggest 19 million people in the US take fish oil supplements
• Benefits claimed on: heart, brain, weight, vision, inflammation, skin,

pregnancy, liver fat, depression, childhood behaviour, mental decline, allergies, bones…

• Environmental costs debated

Summary: Omega-3 FA supplementation in diabetes

• ASCEND is the largest and longest duration placebo-controlled

randomized trial of omega-3 FA supplementation

• No effect on primary outcome of serious vascular events
• No effect on cancer, total or cause-specific mortality
• No safety concerns

Guideline recommendations should be reconsidered